Although effective therapies are available for the treatment of depression, the molecular mechanisms and neural substrates that underlie the path physiology of this disease are still largely unknown. Recent studies have shown an increase in cAMP-response element binding protein (CREB) in the amygdala following antidepressant administration, which may contribute to the therapeutic effects of these drugs. The amgdala is critical in mediating the physiological responses to stress, fear and anxiety. Moreover, clinical studies have shown that there is an increase in function in the amygdala of depressed patients, further implicating this brain region in depression. Our lab has generated a transgenic mouse that expresses a dominant negative mutant of CREB (mCREB) within the amygdala. These mice exhibit a fearful and anxious phenotype when tested in behavioral models as compared to control mice. We hypothesize that mice expressing mCREB within the amygdala show enhanced sensitivity to aversive stimuli that results in a depressed phenotype when tested in various behavioral models of depression. We are proposing to study the effects of chronic antidepressant administration on the mCREB mice and to determine a potential neurochemical mechanism by which these mice show increased responsiveness to stressful stimuli. These mice may serve as novel model for studying the role of the amygdala in depression.